Clinically, most antidepressant drugs require 3 weeks of administration to be effective in alleviating depression. In animals, chronic but not acute antidepressant treatments alter the binding characteristics in brain tissues of ligands related to neurotransmitters, particularly norepinephrine, serotonin, and acetylcholine. To assess the functional relevance of these ligand-binding changes in rats, we propose to examine the effects of acute and chronic antidepressants on the behavioral effects of hippocampal microinfusions of norepinephrine, serotonin, and the cholinergic agonist carbachol. Using a new behavioral pattern monitor which reveals quantitative and qualitative changes in locomotor activity and investigatory behavior, we have already described dose-dependent behavioral effects specifically reflective of the activation of either beta-noradrenergic or muscarinic-cholinergic synapses in the dentate gyrus of the dorsal hippocampus. Studies are proposed to similarly characterize the effects of serotonin infusions, with neurotoxin lesions of the raphe nuclei being used to confirm the specificity of these effects. The distribution of the infusate and the extent of lesions will be assessed with quantitative fluorescence histochemistry and liquid chromatography with electrochemical detection. The functional status of the serotonergic, beta-adrenergic, and muscarinic-cholinergic inputs to the hippocampus will be assessed behaviorally after one or 21 daily oral treatments with four disparate antidepressants: desmethyl-imipramine; imipramine; trazodone; and mianserin. Appropriate ligand-binding studies will be done on the hippocampi from the same rats to confirm the expected changes due to the antidepressants. These studies should establish the functional significance at a behavioral level of the ligand-binding changes induced by antidepressants, and increase our understanding of the brain mechanisms responsible for their therapeutic actions in humans.